Single-cell RNA sequencing-derived signatures define response patterns to atezolizumab + bevacizumab in advanced hepatocellular carcinoma

Background & Aims The combination of atezolizumab and bevacizumab (atezo+bev) is the current standard of care for advanced hepatocellular carcinoma (HCC), providing a median overall survival (OS) of 19.2 months. Here, we aim to uncover the underlying cellular processes driving clinical benefit v...

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Detalles Bibliográficos
Autores: Cappuyns, Sarah, Piqué-Gili, Marta, Esteban-Fabró, Roger, Philips, Gino, Balaseviciute, Ugne, Pinyol, Roser, Gris-Oliver, Albert, Vandecaveye, Vincent, Abril-Fornaguera, Jordi, Montironi, Carla, Bassaganyas, Laia, Peix, Judit, Zeitlhoefle, Marcus, Mesropian, Agavni, Huguet-Pradell, Júlia, Haber, Philipp K., Figueiredo, Igor, Ioannou, Giorgio, Gonzalez-Kozlova, Edgar, D’Alessio, Antonio, Mohr, Raphae, Meyer, Tim, Lachenmayer, Anja, Marquardt, Jens U., Reeves, Helen L., Edeline, Julien, Finkelmeier, Fabian, Trojan, Jörg, Galle, Peter R., Foerster, Friedrich, Mínguez, Beatriz, Montal Roura, Robert, Gnjatic, Sacha, Pinato, David J., Heikenwalder, Mathias, Verslype, Chris, Van Cutsem, Eric, Lambrechts, Diether, Villanueva, Augusto, Dekervel, Jeroen, Llovet, Josep M.
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2025
País:España
Institución:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repositorio:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:recercat.cat:10459.1/468218
Acceso en línea:https://doi.org/10.1016/j.jhep.2024.12.016
https://hdl.handle.net/10459.1/468218
Access Level:acceso abierto
Palabra clave:Advanced Hepatocellular Carcinoma
Atezolizumab and bevacizumab
Biomarkers of Response
Descripción
Sumario:Background & Aims The combination of atezolizumab and bevacizumab (atezo+bev) is the current standard of care for advanced hepatocellular carcinoma (HCC), providing a median overall survival (OS) of 19.2 months. Here, we aim to uncover the underlying cellular processes driving clinical benefit vs. resistance to atezo+bev. Methods We harnessed the power of single-cell RNA sequencing in advanced HCC to derive gene expression signatures recapitulating 21 cell phenotypes. These signatures were applied to 422 RNA-sequencing samples of patients with advanced HCC treated with atezo+bev (n = 317) vs. atezolizumab (n = 47) or sorafenib (n = 58) as comparators. Results We unveiled two distinct patterns of response to atezo+bev. First, an immune-mediated response characterised by the combined presence of CD8+ T effector cells and pro-inflammatory CXCL10+ macrophages, representing an immune-rich microenvironment. Second, a non-immune, angiogenesis-related response distinguishable by a reduced expression of the VEGF co-receptor neuropilin-1 (NRP1), a biomarker that specifically predicts improved OS upon atezo+bev vs. sorafenib (p = 0.039). Primary resistance was associated with an enrichment of immunosuppressive myeloid populations, namely CD14+ monocytes and TREM2+ macrophages, and Notch pathway activation. Based on these mechanistic insights we define "Immune-competent" and "Angiogenesis-driven" molecular subgroups, each associated with a significantly longer OS with atezo+bev vs. sorafenib (p of interaction = 0.027), and a “Resistant” subset. Conclusion Our study unveils two distinct molecular subsets of clinical benefit to atezolizumab plus bevacizumab in advanced HCC (“Immune-competent” and “Angiogenesis-driven”) as well as the main traits of primary resistance to this therapy, thus providing a molecular framework to stratify patients based on clinical outcome and guiding potential strategies to overcome resistance.

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